ABSTRACT Despite a significant reduction of major vascular events through the use of statins, cardiovascular disease (CVD) continues to be the leading cause of death. New strategies to address the residual risks include combination therapy of statins with ezetimibe or PCSK9 inhibition. Recent clinical findings indicate that, although effective in further reducing LDL-C, combination therapies do not proportionally translate in reduction of CV events, likely from the relatively high plasma triglycerides still present. Furthermore, some patients cannot reach the low LDL-C target levels or are drug intolerant and TG treatment is difficult. These challenges highlight the need for new targets for intervention and novel therapeutic approaches for dyslipidemia. In vitro and in mice models, IDOL was identified as an E3 ubiquitin ligase targeting LDLR, VLDLR and ApoER2 for degradation and regulating plasma lipid homeostasis independently of PCSK9. Furthermore, in genetic epidemiology studies IDOL was highly associated with LDL-C and CVD outcomes and loss-of-function alleles result in extremely low LDL-C and reduced CVD risk. Unfortunately, intrinsic differences in IDOL biology between mice and primates, create the need to develop an animal model that better approximates human IDOL biology in order to advance IDOL research into the translational arena. Our preliminary studies indicate that rabbits constitute a better model to test the feasibility of IDOL as a clinically relevant target for hyperlipidemia and CVD. Indeed, unlike in mice, rabbit IDOL is induced in the liver in response to LXR agonists, same as in monkeys and humans. IDOL knock-out rabbits have decreased LDL-C and upon high fat high cholesterol diet, maintain low total cholesterol and low triglycerides. We will test the hypothesis that reduced IDOL protein expression levels or activity -through gene deficiency or small molecule inhibitors- will increase plasma lipid clearance, reduce hypercholesterolemia, hypertriglyceridemia and inflammation, resulting in reduced atherosclerosis. Using IDOL knock-out, heterozygous and wild type rabbits, we will establish IDOL as a therapeutic target for reducing atherosclerosis in Aim 1, to study IDOL contribution to liver-mediated plasma lipid clearance, diet-induced atherosclerosis in aorta and coronary artery and the effects of newly developed small molecule IDOL inhibitors. In Aim 2, we will deepen the characterization of IDOL KO effects of the physiology of lipid handling and using primary rabbit cells we will define IDOL-dependent mechanisms in hepatocytes underlying lipid clearance and the response in vitro to novel IDOL inhibitors. Human iPSC-derived hepatocytes and macrophages combined with gain- and loss-of-function will address conservation of the mechanisms across species. Completion of these aims by leveraging new IDOL rabbit models to overcome the current barriers to advance IDOL translational research will provide compelling evidences and new findings to enable IDOL translational research as a novel feasible target for development of focused interventions for hyperlipidemia and CVD management in order to further reduce the overall global impact of CVD.